tbuckley/cabot-search huggingface dataset:
Intricacies of TGF-β signaling in Treg and Th17 cell biology
Authors: Junying Wang, Xingqi Zhao, Yisong Y. Wan
Journal: Cellular and Molecular Immunology (2023)

Balanced immunity is pivotal for health and homeostasis. CD4+ helper T (Th) cells are central to the balance between immune tolerance and immune rejection. Th cells adopt distinct functions to maintain tolerance and clear pathogens. Dysregulation of Th cell function often leads to maladies, including autoimmunity, inflammatory disease, cancer, and infection. Regulatory T (Treg) and Th17 cells are critical Th cell types involved in immune tolerance, homeostasis, pathogenicity, and pathogen clearance. It is therefore critical to understand how Treg and Th17 cells are regulated in health and disease. Cytokines are instrumental in directing Treg and Th17 cell function. The evolutionarily conserved TGF-β (transforming growth factor-β) cytokine superfamily is of particular interest because it is central to the biology of both Treg cells that are predominantly immunosuppressive and Th17 cells that can be proinflammatory, pathogenic, and immune regulatory. How TGF-β superfamily members and their intricate signaling pathways regulate Treg and Th17 cell function is a question that has been intensely investigated for two decades. Here, we introduce the fundamental biology of TGF-β superfamily signaling, Treg cells, and Th17 cells and discuss in detail how the TGF-β superfamily contributes to Treg and Th17 cell biology through complex yet ordered and cooperative signaling networks.
Flexible neural control of transition points within the egg-laying behavioral sequence in Drosophila
Authors: Kevin M. Cury, Richard Axel
Journal: Nature Neuroscience (2023)

Abstract Innate behaviors are frequently comprised of ordered sequences of component actions that progress to satisfy essential drives. Progression is governed by specialized sensory cues that induce transitions between components within the appropriate context. Here we have characterized the structure of the egg-laying behavioral sequence in Drosophila and found significant variability in the transitions between component actions that affords the organism an adaptive flexibility. We identified distinct classes of interoceptive and exteroceptive sensory neurons that control the timing and direction of transitions between the terminal components of the sequence. We also identified a pair of motor neurons that enact the final transition to egg expulsion. These results provide a logic for the organization of innate behavior in which sensory information processed at critical junctures allows for flexible adjustments in component actions to satisfy drives across varied internal and external environments.
Metabolic landscape of the male mouse gut identifies different niches determined by microbial activities
Authors: Karin H. U. Meier, Julian Trouillon, Hai Li, Melanie Lang, Tobias Fuhrer, Nicola Zamboni, Shinichi Sunagawa, Andrew J. Macpherson, Uwe Sauer
Journal: Nature Metabolism (2023)

Abstract Distinct niches of the mammalian gut are populated by diverse microbiota, but the contribution of spatial variation to intestinal metabolism remains unclear. Here we present a map of the longitudinal metabolome along the gut of healthy colonized and germ-free male mice. With this map, we reveal a general shift from amino acids in the small intestine to organic acids, vitamins and nucleotides in the large intestine. We compare the metabolic landscapes in colonized versus germ-free mice to disentangle the origin of many metabolites in different niches, which in some cases allows us to infer the underlying processes or identify the producing species. Beyond the known impact of diet on the small intestinal metabolic niche, distinct spatial patterns suggest specific microbial influence on the metabolome in the small intestine. Thus, we present a map of intestinal metabolism and identify metabolite–microbe associations, which provide a basis to connect the spatial occurrence of bioactive compounds to host or microorganism metabolism.
Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes
Authors: Paula Cunnea, Edward W. Curry, Elizabeth L. Christie, Katherine Nixon, Chun Hei Kwok, Ahwan Pandey, Ratri Wulandari, Kerstin Thol, Jennifer Ploski, Cristina Morera-Albert, Stephen McQuaid, Jingky Lozano-Kuehne, James J. Clark, Jonathan Krell, Euan A. Stronach, Iain A. McNeish, David D.L. Bowtell, Christina Fotopoulou
Journal: Cell Reports Medicine (2023)

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making.
Cancer cachexia: molecular mechanisms and treatment strategies
Authors: Tania Setiawan, Ita Novita Sari, Yoseph Toni Wijaya, Nadya Marcelina Julianto, Jabir Aliyu Muhammad, Hyeok Lee, Ji Heon Chae, Hyog Young Kwon
Journal: Journal of Hematology & Oncology (2023)

Abstract Muscle wasting is a consequence of physiological changes or a pathology characterized by increased catabolic activity that leads to progressive loss of skeletal muscle mass and strength. Numerous diseases, including cancer, organ failure, infection, and aging-associated diseases, are associated with muscle wasting. Cancer cachexia is a multifactorial syndrome characterized by loss of skeletal muscle mass, with or without the loss of fat mass, resulting in functional impairment and reduced quality of life. It is caused by the upregulation of systemic inflammation and catabolic stimuli, leading to inhibition of protein synthesis and enhancement of muscle catabolism. Here, we summarize the complex molecular networks that regulate muscle mass and function. Moreover, we describe complex multi-organ roles in cancer cachexia. Although cachexia is one of the main causes of cancer-related deaths, there are still no approved drugs for cancer cachexia. Thus, we compiled recent ongoing pre-clinical and clinical trials and further discussed potential therapeutic approaches for cancer cachexia.
Phenotypic diversity of T cells in human primary and metastatic brain tumors revealed by multiomic interrogation
Authors: Vladimir Wischnewski, Roeltje R. Maas, Paola Guerrero Aruffo, Klara Soukup, Giovanni Galletti, Mara Kornete, Sabine Galland, Nadine Fournier, Johanna Lilja, Pratyaksha Wirapati, Joao Lourenco, Alice Scarpa, Roy T. Daniel, Andreas F. Hottinger, Jean-Philippe Brouland, Agnese Losurdo, Emanuele Voulaz, Marco Alloisio, Monika E. Hegi, Enrico Lugli, Johanna A. Joyce
Journal: Nature Cancer (2023)

Abstract The immune-specialized environment of the healthy brain is tightly regulated to prevent excessive neuroinflammation. However, after cancer development, a tissue-specific conflict between brain-preserving immune suppression and tumor-directed immune activation may ensue. To interrogate potential roles of T cells in this process, we profiled these cells from individuals with primary or metastatic brain cancers via integrated analyses on the single-cell and bulk population levels. Our analysis revealed similarities and differences in T cell biology between individuals, with the most pronounced differences observed in a subgroup of individuals with brain metastasis, characterized by accumulation of CXCL13 -expressing CD39 + potentially tumor-reactive T (pTRT) cells. In this subgroup, high pTRT cell abundance was comparable to that in primary lung cancer, whereas all other brain tumors had low levels, similar to primary breast cancer. These findings indicate that T cell-mediated tumor reactivity can occur in certain brain metastases and may inform stratification for treatment with immunotherapy.
The NR_109/FUBP1/c-Myc axis regulates TAM polarization and remodels the tumor microenvironment to promote cancer development
Authors: Cong Zhang, Sisi Wei, Suli Dai, Xiaoya Li, Huixia Wang, Hongtao Zhang, Guogui Sun, Baoen Shan, Lianmei Zhao
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background Tumor-associated macrophages (TAMs) are a major component of the tumor microenvironment (TME) and exert an important role in tumor progression. Due to the heterogeneity and plasticity of TAMs, modulating the polarization states of TAMs is considered as a potential therapeutic strategy for tumors. Long noncoding RNAs (lncRNAs) have been implicated in various physiological and pathological processes, yet the underlying mechanism on how lncRNAs manipulate the polarization states of TAMs is still unclear and remains to be further investigated. Methods Microarray analyses were employed to characterize the lncRNA profile involved in THP-1-induced M0, M1 and M2-like macrophage. Among those differentially expressed lncRNAs, NR_109 was further studied, for its function in M2-like macrophage polarization and the effects of the condition medium or macrophages mediated by NR_109 on tumor proliferation, metastasis and TME remodeling both in vitro and in vivo. Moreover, we revealed how NR_109 interacted with far upstream element-binding protein 1 (FUBP1) to regulate the protein stability through hindering ubiquitination modification by competitively binding with JVT-1. Finally, we examined sections of tumor patients to probe the correlation among the expression of NR_109 and related proteins, showing the clinical significance of NR_109. Results We found that lncRNA NR_109 was highly expressed in M2-like macrophages. Knockdown NR_109 impeded IL-4 induced M2-like macrophage polarization and significantly reduced the activity of M2-like macrophages to support the proliferation and metastasis of tumor cells in vitro and in vivo. Mechanistically, NR_109 competed with JVT-1 to bind FUBP1 at its C-terminus domain, impeded the ubiquitin-mediated degradation of FUBP1, activated c-Myc transcription and thus promoted M2-like macrophages polarization. Meanwhile, as a transcription factor, c-Myc could bind to the promoter of NR_109 and enhance the transcription of NR_109. Clinically, high NR_109 expression was found in CD163 + TAMs from tumor tissues and was positively correlated with poor clinical stages of patients with gastric cancer and breast cancer. Conclusions Our work revealed for the first time that NR_109 exerted a crucial role in regulating the phenotype-remodeling and function of M2-like macrophages via a NR_109/FUBP1/c-Myc positive feedback loop. Thus, NR_109 has great translational potentials in the diagnosis, prognosis and immunotherapy of cancer.
The wheat stem rust resistance gene Sr43 encodes an unusual protein kinase
Authors: Guotai Yu, Oadi Matny, Spyridon Gourdoupis, Naganand Rayapuram, Fatimah R. Aljedaani, Yan L. Wang, Thorsten Nürnberger, Ryan Johnson, Emma E. Crean, Isabel M.-L. Saur, Catherine Gardener, Yajuan Yue, Ngonidzashe Kangara, Burkhard Steuernagel, Sadiye Hayta, Mark Smedley, Wendy Harwood, Mehran Patpour, Shuangye Wu, Jesse Poland, Jonathan D. G. Jones, T. Lynne Reuber, Moshe Ronen, Amir Sharon, Matthew N. Rouse, Steven Xu, Kateřina Holušová, Jan Bartoš, István Molnár, Miroslava Karafiátová, Heribert Hirt, Ikram Blilou, Łukasz Jaremko, Jaroslav Doležel, Brian J. Steffenson, Brande B. H. Wulff
Journal: Nature Genetics (2023)

Abstract To safeguard bread wheat against pests and diseases, breeders have introduced over 200 resistance genes into its genome, thus nearly doubling the number of designated resistance genes in the wheat gene pool 1 . Isolating these genes facilitates their fast-tracking in breeding programs and incorporation into polygene stacks for more durable resistance. We cloned the stem rust resistance gene Sr43 , which was crossed into bread wheat from the wild grass Thinopyrum elongatum 2,3 . Sr43 encodes an active protein kinase fused to two domains of unknown function. The gene, which is unique to the Triticeae, appears to have arisen through a gene fusion event 6.7 to 11.6 million years ago. Transgenic expression of Sr43 in wheat conferred high levels of resistance to a wide range of isolates of the pathogen causing stem rust, highlighting the potential value of Sr43 in resistance breeding and engineering.
Long-term follow-up of anti-PD-1 naïve patients with metastatic melanoma treated with IDO/PD-L1 targeting peptide vaccine and nivolumab
Authors: Cathrine Lund Lorentzen, Julie Westerlin Kjeldsen, Eva Ehrnrooth, Mads Hald Andersen, Inge Marie Svane
Journal: Journal for ImmunoTherapy of Cancer (2023)

We have previously published initial efficacy of the indoleamine 2,3-dioxygenase (IDO)/anti-programmed death ligand 1 (PD-L1) vaccine in combination with nivolumab in 30 anti-PD-1 therapy naïve patients with metastatic melanoma (cohort A). We now report long-term follow-up of patients in cohort A. Further, we report results from cohort B, where the peptide vaccine was added to anti-PD-1 therapy for patients with progressive disease during anti-PD-1 treatment.
Longitudinal evolution of cortical thickness signature reflecting Lewy body dementia in isolated REM sleep behavior disorder: a prospective cohort study
Authors: Jung Hwan Shin, Heejung Kim, Yu Kyeong Kim, Eun Jin Yoon, Hyunwoo Nam, Beomseok Jeon, Jee-Young Lee
Journal: Translational Neurodegeneration (2023)

The isolated rapid-eye-movement sleep behavior disorder (iRBD) is a prodromal condition of Lewy body disease including Parkinson's disease and dementia with Lewy bodies (DLB). We aim to investigate the longitudinal evolution of DLB-related cortical thickness signature in a prospective iRBD cohort and evaluate the possible predictive value of the cortical signature index in predicting dementia-first phenoconversion in individuals with iRBD.We enrolled 22 DLB patients, 44 healthy controls, and 50 video polysomnography-proven iRBD patients. Participants underwent 3-T magnetic resonance imaging (MRI) and clinical/neuropsychological evaluations. We characterized DLB-related whole-brain cortical thickness spatial covariance pattern (DLB-pattern) using scaled subprofile model of principal components analysis that best differentiated DLB patients from age-matched controls. We analyzed clinical and neuropsychological correlates of the DLB-pattern expression scores and the mean values of the whole-brain cortical thickness in DLB and iRBD patients. With repeated MRI data during the follow-up in our prospective iRBD cohort, we investigated the longitudinal evolution of the cortical thickness signature toward Lewy body dementia. Finally, we analyzed the potential predictive value of cortical thickness signature as a biomarker of phenoconversion in iRBD cohort.The DLB-pattern was characterized by thinning of the temporal, orbitofrontal, and insular cortices and relative preservation of the precentral and inferior parietal cortices. The DLB-pattern expression scores correlated with attentional and frontal executive dysfunction (Trail Making Test-A and B: R = - 0.55, P = 0.024 and R = - 0.56, P = 0.036, respectively) as well as visuospatial impairment (Rey-figure copy test: R = - 0.54, P = 0.0047). The longitudinal trajectory of DLB-pattern revealed an increasing pattern above the cut-off in the dementia-first phenoconverters (Pearson's correlation, R = 0.74, P = 6.8 × 10-4) but no significant change in parkinsonism-first phenoconverters (R = 0.0063, P = 0.98). The mean value of the whole-brain cortical thickness predicted phenoconversion in iRBD patients with hazard ratio of 9.33 [1.16-74.12]. The increase in DLB-pattern expression score discriminated dementia-first from parkinsonism-first phenoconversions with 88.2% accuracy.Cortical thickness signature can effectively reflect the longitudinal evolution of Lewy body dementia in the iRBD population. Replication studies would further validate the utility of this imaging marker in iRBD.
Standard-dose versus double-dose dolutegravir in HIV-associated tuberculosis in South Africa (RADIANT-TB): a phase 2, non-comparative, randomised controlled trial
Authors: Rulan Griesel, Ying Zhao, Bryony Simmons, Zaayid Omar, Lubbe Wiesner, Claire M Keene, Andrew M Hill, Graeme Meintjes, Gary Maartens
Journal: The Lancet HIV (2023)

<h2>Summary</h2><h3>Background</h3> The drug–drug interaction between rifampicin and dolutegravir can be overcome by supplemental dolutegravir dosing, which is difficult to implement in high-burden settings. We aimed to test whether virological outcomes with standard-dose dolutegravir-based antiretroviral therapy (ART) are acceptable in people with HIV on rifampicin-based antituberculosis therapy. <h3>Methods</h3> RADIANT-TB was a phase 2b, randomised, double-blind, non-comparative, placebo-controlled trial at a single site in Khayelitsha, Cape Town, South Africa. Participants were older than 18 years of age, with plasma HIV-1 RNA greater than 1000 copies per mL, CD4 count greater than 100 cells per μL, ART-naive or first-line ART interrupted, and on rifampicin-based antituberculosis therapy for less than 3 months. By use of permuted block (block size of 6) randomisation, participants were assigned (1:1) to receive either tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus supplemental 50 mg dolutegravir 12 h later or tenofovir disoproxil fumarate, lamivudine, and dolutegravir plus matched placebo 12 h later. Participants received standard antituberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol for the first 2 months followed by isoniazid and rifampicin for 4 months). The primary outcome was the proportion of participants with virological suppression (HIV-1 RNA <50 copies per mL) at week 24 analysed in the modified intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03851588. <h3>Findings</h3> Between Nov 28, 2019, and July 23, 2021, 108 participants (38 female, median age 35 years [IQR 31–40]) were randomly assigned to supplemental dolutegravir (n=53) or placebo (n=55). Median baseline CD4 count was 188 cells per μL (IQR 145–316) and median HIV-1 RNA was 5·2 log<sub>10</sub> copies per mL (4·6–5·7). At week 24, 43 (83%, 95% CI 70–92) of 52 participants in the supplemental dolutegravir arm and 44 (83%, 95% CI 70–92) of 53 participants in the placebo arm had virological suppression. No treatment-emergent dolutegravir resistance mutations were detected up to week 48 in the 19 participants with study-defined virological failure. Grade 3 and 4 adverse events were similarly distributed between the study arms. The most frequent grade 3 and 4 adverse events were weight loss (4/108 [4%]), insomnia (3/108 [3%]), and pneumonia (3/108 [3%]). <h3>Interpretation</h3> Our findings suggest that twice-daily dolutegravir might be unnecessary in people with HIV-associated tuberculosis. <h3>Funding</h3> Wellcome Trust.
An unusual tandem kinase fusion protein confers leaf rust resistance in wheat
Authors: Yajun Wang, Michael Abrouk, Spyridon Gourdoupis, Dal-Hoe Koo, Miroslava Karafiátová, István Molnár, Kateřina Holušová, Jaroslav Doležel, Naveenkumar Athiyannan, Emile Cavalet-Giorsa, Łukasz Jaremko, Jesse Poland, Simon G. Krattinger
Journal: Nature Genetics (2023)

The introgression of chromosome segments from wild relatives is an established strategy to enrich crop germplasm with disease-resistance genes1. Here we use mutagenesis and transcriptome sequencing to clone the leaf rust resistance gene Lr9, which was introduced into bread wheat from the wild grass species Aegilops umbellulata2. We established that Lr9 encodes an unusual tandem kinase fusion protein. Long-read sequencing of a wheat Lr9 introgression line and the putative Ae. umbellulata Lr9 donor enabled us to assemble the ~28.4-Mb Lr9 translocation and to identify the translocation breakpoint. We likewise cloned Lr58, which was reportedly introgressed from Aegilops triuncialis3, but has an identical coding sequence compared to Lr9. Cytogenetic and haplotype analyses corroborate that the two genes originate from the same translocation event. Our work sheds light on the emerging role of kinase fusion proteins in wheat disease resistance, expanding the repertoire of disease-resistance genes for breeding.
A systematic review of psychosocial functioning changes after gender-affirming hormone therapy among transgender people
Authors: David Matthew Doyle, Tom O. G. Lewis, Manuela Barreto
Journal: Nature Human Behaviour (2023)

Abstract This systematic review assessed the state and quality of evidence for effects of gender-affirming hormone therapy on psychosocial functioning. Forty-six relevant journal articles (six qualitative, 21 cross-sectional, 19 prospective cohort) were identified. Gender-affirming hormone therapy was consistently found to reduce depressive symptoms and psychological distress. Evidence for quality of life was inconsistent, with some trends suggesting improvements. There was some evidence of affective changes differing for those on masculinizing versus feminizing hormone therapy. Results for self-mastery effects were ambiguous, with some studies suggesting greater anger expression, particularly among those on masculinizing hormone therapy, but no increase in anger intensity. There were some trends toward positive change in interpersonal functioning. Overall, risk of bias was highly variable between studies. Small samples and lack of adjustment for key confounders limited causal inferences. More high-quality evidence for psychosocial effects of gender-affirming hormone therapy is vital for ensuring health equity for transgender people.
SeATAC: a tool for exploring the chromatin landscape and the role of pioneer factors
Authors: Wuming Gong, Nikita Dsouza, Daniel J. Garry
Journal: Genome biology (2023)

Abstract Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) reveals chromatin accessibility across the genome. Currently, no method specifically detects differential chromatin accessibility. Here, SeATAC uses a conditional variational autoencoder model to learn the latent representation of ATAC-seq V-plots and outperforms MACS2 and NucleoATAC on six separate tasks. Applying SeATAC to several pioneer factor-induced differentiation or reprogramming ATAC-seq datasets suggests that induction of these factors not only relaxes the closed chromatin but also decreases chromatin accessibility of 20% to 30% of their target sites. SeATAC is a novel tool to accurately reveal genomic regions with differential chromatin accessibility from ATAC-seq data.